KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.

Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.

Obesity-Associated GNAS Mutations and the Melanocortin Pathway.

BACKGROUND: GNAS encodes the Gαs (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. GNAS mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism). METHODS: We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 GNAS mutation carriers. We investigated whether the effect of GNAS mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays. RESULTS: Almost all GNAS mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, -0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. GNAS mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have GNAS mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONS: Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for GNAS deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. GNAS mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.).

Parental concerns about genital differences in children with congenital adrenal hyperplasia persist regardless of the selected intervention.

BACKGROUND: Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency (21HD) can affect the in utero development of the genital anatomy of people with the 46XX karyotype. Health professionals engage parents in decision-making regarding managing genitals with this difference, including genital surgery options and patient communication. AIM: We sought to investigate parental communication with their daughters regarding clitoral size variation related to neonatal CAH. METHODS: Semistructured in-person interviews of 24 parents of chromosomal XX children with clitoral size variation attributable to a neonatal CAH diagnosis comprised 3 management categories: (1) clitoral reduction surgery (RS) (7 parents, 9 children), (2) clitoral concealment surgery (CS) (8 parents, 8 children), and no surgery on or around the clitoris (NS) (9 parents, 7 children). OUTCOMES: Four representative themes, Obvious Choice, Still Different, Parental Burden, and Ignorance Is Bliss, were common across all 3 treatment groups. RESULTS: For most parents, none of the 3 options of genital appearance alteration via clitoral reduction, clitoral concealment surgery, or avoidance of clitoral surgery ameliorated concerns, with most parents expressing an aversion to educating their child on the topic of genital differences, past treatment, or future function. CLINICAL IMPLICATIONS: Reliance on surgical treatment pathways to manage this psychosocial concern is ineffective in alleviating parental uncertainty without the application of psychosocial interventions. STRENGTHS AND LIMITATIONS: This was a qualitative study but was limited to parents of children with a specific genital difference, without direct exploration of parental values regarding the clitoris or the application of adequate psychosocial care. CONCLUSION: Healthcare services must have an impact on parental ability to engage in essential communication with their children in cases such as clitoral size variation related to neonatal CAH. Improved communication skills allow parents to engage in more genuine decision-making and adapt to enduring genital reality, including possible future sexual challenges for their adult child, without resorting to burdensome strategies focused on attempts to perpetuate a benevolent ignorance.

Correlating measured radiotherapy dose with patterns of endocrinopathy: The importance of minimizing pituitary dose.

BACKGROUND: Pituitary insufficiency is a common toxicity of cranial radiotherapy received in childhood for central nervous system, head and neck, and hematological malignancies. There is a recognized deficiency pattern and correlation with prescribed radiotherapy dose; however, correlation with measured pituitary dose (which can be minimized with modern radiotherapy techniques) has not previously been assessed. PROCEDURE: Retrospective analysis was carried out of measured pituitary dose and endocrine outcomes of patients receiving cranial, total body, or head and neck photon beam radiotherapy at a tertiary center from July 2008 to October 2019. RESULTS: Complete data for 102 patients were available. Median (IQR) age at radiotherapy was 9.0 (6.0-12.0) and follow-up 5.7 years (3.5-9.1). Most patients received focal brain radiotherapy (36.3%) or total body irradiation (32.4%); most frequent diagnoses were acute lymphoblastic leukemia (25.5%) and medulloblastoma (17.6%). The majority developed pituitary insufficiency (64; 62.7%); 41% had one and 38% had two hormone deficiencies. Growth hormone deficiency (GHD) (58; 56.9%) and thyroid-stimulating hormone deficiency (TSHD) (32; 31.4%) were most common. Patients who developed pituitary insufficiency received higher maximum pituitary dose-median (IQR) Gy, 44.0 (20.4-54.0) vs 18.2 (14.4-52.6); P = 0.008. Doses of 40-49 Gy or >50 Gy led to a higher cumulative incident rate than <20 Gy (HR 4.07, P < 0.001 and HR 3.04, P < 0.001, respectively). However, even at lower dose bands, levels of pituitary insufficiency were significant with a five-year cumulative incidence of GHD for <20 Gy and TSHD for 20-29 Gy reaching >30%. CONCLUSIONS: Our findings confirm a correlation between measured pituitary dose and risk of insufficiency even at lower doses, despite modern radiotherapy techniques. These data highlight the importance of minimizing pituitary dose and early specialist endocrine follow-up.

Combined resistance and aerobic exercise intervention improves fitness, insulin resistance and quality of life in survivors of childhood haemopoietic stem cell transplantation with total body irradiation.

PURPOSE: To investigate the effects of a supervised combined resistance and aerobic training programme on cardiorespiratory fitness, body composition, insulin resistance and quality of life (QoL) in survivors of childhood haematopoietic stem cell transplantation (HSCT) with total body irradiation (TBI). PARTICIPANTS: HSCT/TBI survivors (n = 20; 8 females). Mean (range) for age at study and time since HSCT/TBI was 16.7 (10.9-24.5) and 8.4 (2.3-16.0) years, respectively. METHODS: After a 6-month run-in, participants undertook supervised 45- to 60-minute resistance and aerobic training twice weekly for 6 months, with a 6-month follow-up. The following assessments were made at 0, 6 (start of exercise programme), 12 (end of exercise programme) and 18 months: Body composition via dual energy X-ray absorptiometry, homeostatic model assessment of insulin resistance (HOMA-IR), cardiorespiratory fitness (treadmill-based peak rate of oxygen uptake (VO2 peak) test), QoL questionnaires (36-Item Short Form Health Survey (SF-36) and Minneapolis-Manchester Quality of Life Instrument (MMQL). RESULTS: Results expressed as mean (standard deviation) or geometric mean (range). There were significant improvements in VO2 peak (35.7 (8.9) vs 41.7 (16.1) mL/min/kg, P = 0.05), fasted plasma insulin (16.56 (1.48-72.8) vs 12.62 (1.04-54.97) mIU/L, P = 0.03) and HOMA-IR (3.65 (0.30-17.26) vs 2.72 (0.22-12.89), P = 0.02) after the exercise intervention. There were also significant improvements in the SF-36 QoL general health domain (69.7 (14.3) vs 72.7 (16.0), P = 0.001) and the MMQL school domain (69.1 (25.2) vs (79.3 (21.6), P = 0.03) during the exercise intervention. No significant changes were observed in percentage body fat, fat mass or lean mass. CONCLUSION: The supervised 6-month combined resistance and aerobic exercise programme significantly improved cardiorespiratory fitness, insulin resistance and QoL in childhood HSCT/TBI survivors, with no change in body composition, suggesting a metabolic training effect on muscle. These data support a role for targeted physical rehabilitation services in this group at high risk of diabetes and cardiovascular disease.

Cognitive behavioural therapy stabilises glycaemic control in adolescents with type 1 diabetes-Outcomes from a randomised control trial.

BACKGROUND: To compare the impact of cognitive behavioural therapy (CBT) with non-directive supportive counselling (NDC) on glycaemic control and psychological well-being in adolescents with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: Participants aged 11 to 16 years with T1DM (duration ≥1 year) from 4 UK-based paediatric diabetes centres were randomised to receive either 6 weekly sessions of 1-to-1 CBT (n = 43) or NDC (n = 42), with 2 further sessions at 6 and 12 months. Follow-up continued for 12 months postintervention. Outcome measures included glycated haemoglobin A1c (HbA1c) and psychological scores. RESULTS: The HbA1c levels were available in 33 patients in each group for analysis. Between group difference of the overall changes in HbA1c across the study period was statically significant (P = .018). Geometric mean (range) HbA1c in the NDC group deteriorated from 68 (46-113) to 78 (48-128) mmol/mol (ie, 8.4 [6.4-12.5]% to 9.3 [6.5-13.9]%; P = .001), but was maintained in the CBT group from 72 (46-129) to 73 (51-128) mmol/mol (P = .51) (ie, 8.7 [6.4-14]% to 8.9 [6.8-13.9]%). More patients who have undergone CBT showed an improved or maintained HbA1c levels at 24 months (62.5% vs 35.5%, P = .032). Patients offered CBT with depressive scores in the lowest tertile (least depressive symptoms) showed improvement in HbA1c over time from 70 (46-102) to 67 (57-87) mmol/mol (P = .041) (ie, 8.6 [6.4-11.5]% to 8.3 [7.4-10.1]%), but not in the NDC group. The CBT showed borderline improvements in Children's Health Locus of Control (internal) scores over time compared with NDC (P = .05). The self-efficacy score showed significant improvement in both CBT (P < .001) and NDC (P = .03) groups over time. CONCLUSIONS: CBT demonstrated better maintenance of glycaemic control compared with NDC.

Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2.

Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence of these disorders (HIPKD) in 17 children from 11 unrelated families suggested an unrecognized genetic disorder. Whole-genome linkage analysis in five informative families identified a single significant locus on chromosome 16p13.2 (logarithm of odds score 6.5). Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, we found in all patients a promoter mutation (c.-167G>T) in the phosphomannomutase 2 gene (PMM2), either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic ß cells altered insulin secretion. Recessive coding mutations in PMM2 cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multisystem disorder with prominent neurologic involvement. Yet our patients did not exhibit the typical clinical or diagnostic features of CDG1A. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2 We propose that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.

Reduced beta-cell reserve and pancreatic volume in survivors of childhood acute lymphoblastic leukaemia treated with bone marrow transplantation and total body irradiation.

BACKGROUND: Impaired glucose tolerance (IGT) and diabetes mellitus (DM) occur more frequently after bone marrow transplantation and total body irradiation (BMT/TBI), but the mechanism is unclear. This study investigates insulin sensitivity, ß-cell reserve and pancreatic volume in adult survivors of childhood acute lymphoblastic leukaemia (ALL). METHOD: Survivors (aged 16-26 years) of ALL treated with BMT/TBI (10-14·4 Gy) Group 1 (n = 20, 10 m) were compared with a chemotherapy-only Group 2 (n = 28, 11 m). Participants underwent assessments of insulin sensitivity by whole body composite-insulin-sensitivity-index (ISIcomp ) from oral glucose tolerance tests (OGTTs); first (AIRarg , AIRg , AUCin10 ) and second (AUC in second phase ) phase insulin responses from arginine-intravenous glucose tolerance tests; and pancreatic volume by abdominal magnetic resonance imaging (MRI). Data were analysed by odds ratio, Chi-square or Fisher's exact tests, Student's t-tests, analysis of covariance (ancova) and Pearson's or partial correlations (5% significance). RESULTS: Abnormal OGTTs were documented in Group 1 (DM = 2, IGT = 7). Insulin secretion adjusted for insulin sensitivity was lower in Group 1 than Group 2 as a whole [LogAIRarg (P = 0·008), logAIRg (P = 0·013) and logAUCin10 (P = 0·014)] and after exclusion of those with abnormal glucose tolerance [logAIRarg (P = 0·011), logAIRg (P = 0·007) and logAUCin10 (P = 0·006)]. Group 1 had lower pancreatic volume than Group 2 [52·0 (14·2) vs 72·8 (23·5), P = 0·001] cm(3) , and results were consistent after adjustment for size by body surface area (P = 0·019). Pancreatic volume correlated with logAIRarg adjusted log ISIcomp (partial correlation = 0·34, P = 0·025). CONCLUSIONS: Adult survivors of childhood BMT/TBI for ALL demonstrated reduced ß-cell reserve and smaller pancreatic volume, both likely additional aetiological factors, with reduced insulin sensitivity, in their increased risk of diabetes.

Reduced insulin sensitivity in childhood survivors of haematopoietic stem cell transplantation is associated with lipodystropic and sarcopenic phenotypes.

BACKGROUND: Survivors of childhood acute lymphoblastic leukaemia (ALL) treated with haematopoietic stem cell transplantation and total body irradiation (HSCT/TBI) have a high cardiometabolic risk despite lacking overt clinical obesity. This study characterised body composition using different methodologies and explored associations with reduced insulin sensitivities in a group of ALL survivors treated with/without HSCT/TBI. PROCEDURE: Survivors of childhood ALL treated with HSCT/TBI (n = 20,10 M) were compared with Chemotherapy-only (n = 31), and an obese non-leukaemic controls (n = 30). All subjects (aged 16-26 years) were investigated with: auxology (BMI, waist and hip circumferences), DEXA (total and regional fat, fat-free mass), abdominal MRI (subcutaneous, visceral, intramuscular fat), oral glucose tolerance tests (impaired glucose tolerance or diabetes, insulin sensitivity) and serum adiponectin. RESULTS: HSCT/TBI Group displayed a higher prevalence of abnormal glucose tolerance (45%); lower insulin sensitivity; lower lean mass with higher prevalence of reduced fat-free mass index (from DEXA); higher visceral and intramuscular, and lower subcutaneous fat on MRI, compared with the Chemotherapy-only and Obese controls. BMI was lowest in HSCT/TBI Group. Waist-to-hip and android-to-gynoid ratios were similar between HSCT/TBI and Obese Groups. Insulin sensitivity adjusted for visceral fat mass was lower in the HSCT/TBI than the Chemotherapy-only and Obese groups. Adiponectin in the HSCT/TBI Group was lower than the Chemotherapy-only group, and correlated negatively with time post HSCT/TBI. CONCLUSIONS: HSCT/TBI survivors have an increased risk of abnormal glucose tolerance and reduced insulin sensitivity with reduced subcutaneous and increased visceral fat distribution, increased total fat mass and reduced lean mass.

Cortisol dynamics, quality of life and fatigue following traumatic brain injury in childhood.

INTRODUCTION: Traumatic brain injury (TBI) is a leading cause of acquired neurological morbidity. The prevalence of post-traumatic hypopituitarism (PTHP) and associated morbidity after childhood TBI is unclear. Our study investigated long term HPA (hypothalamus-pituitary-adrenal) axis function, in a prospective childhood TBI and control cohort, using measures of cortisol/cortisone secretion (physiological, stimulated), HPA axis feedback and exploring associations with fatigue, depression and Quality of Life (QoL) outcomes. METHODS: All TBI participants had data concerning severity and mechanism of TBI. All groups had clinical assessment, pituitary/brain MRI, questionnaire measures of QoL, fatigue, depression and salivary cortisone profiles including dexamethasone suppression test. In addition participants with Moderate/Severe TBI had ethical approval for baseline endocrine blood tests, overnight 12-hour venous sampling of cortisol and growth hormone, and stimulated HPA axis evaluation with an insulin tolerance test (ITT). RESULTS: Seventy-two participants with moderate/severe (n=31, age 19.8±4.2 years) or mild TBI (n=24, age 17.8±5.1 years) and matched controls (n=17, age 18.5±5.5 years) took part. Time post TBI was 6.8-10.8 years. Baseline endocrine tests confirmed normal thyroid and posterior pituitary function. One female with moderate/severe TBI had hypogonadism. Pituitary neuroimaging was normal in all participants. In 2/25 ITT and 9/22 overnight serum profiles peak cortisol was <500nmol/l. The two participants with suboptimal ITT cortisol response (392 and 483nmol/L) also had low peak spontaneous serum levels (227 and 447nmol/L respectively). Salivary cortisone profiles showed preservation of HPA axis circadian rhythm and suppression with dexamethasone in all but one TBI participant. TBI participants had higher morning salivary cortisone levels compared to controls. Fatigue was reported by 20/46 TBI participants but only 1/14 controls. Fatigue was not associated with stimulated (ITT) or spontaneous (overnight profile) cortisol, however one TBI participant with severe fatigue had a suboptimal ITT cortisol response. Specific QoL attributes of health state (cognition, memory) were impaired in TBI participants compared to controls. CONCLUSION: Although not as prevalent as previously reported, HPA axis dysfunction does occur in survivors of childhood TBI confirming the need for endocrine surveillance. However, in most of our paediatric TBI survivors assessed 7-11 years post-TBI, HPA function and circadian rhythmicity was preserved or had recovered. Chronic fatigue is a common concern post TBI but in the majority not associated with frank HPA axis dysfunction. Morning salivary cortisone levels were higher in TBI survivors, (who have a high prevalence of fatigue) compared to healthy controls, despite the recognised association of chronic fatigue with cortisol hyposecretion.

Evaluating Eating Behaviour, Energy Homeostasis, and Obesity in Childhood-Onset Craniopharyngioma: A Feasibility Study.

INTRODUCTION: Craniopharyngiomas are rare brain tumours (incidence 1.1-1.7 cases/million/year). Although non-malignant, craniopharyngioma causes major endocrine and visual morbidities including hypothalamic obesity, yet mechanisms leading to obesity are poorly understood. This study investigated the feasibility and acceptability of eating behaviour measures in patients with craniopharyngioma to inform the design of future trials. METHODS: Patients with childhood-onset craniopharyngioma and controls matched for sex, pubertal stage, and age were recruited. After an overnight fast, participants received the following measures: body composition, resting metabolic rate, oral glucose tolerance test including magnetic resonance imaging (patients only), appetite ratings, eating behaviour, and quality of life questionnaires, ad libitum lunch, and an acceptability questionnaire. Data are reported as median ± IQR, with effect size measure (Cliff's delta) and Kendall's tau for correlations, due to the small sample size. RESULTS: Eleven patients (median age = 14 years; 5 F/6 M) and matched controls (median age = 12 years; 5 F/6 M) were recruited. All patients had received surgery, and 9/11 also received radiotherapy. Hypothalamic damage post-surgery was graded (Paris grading): grade 2 n = 6; grade 1 n = 1; grade 0 n = 2. The included measures were deemed highly tolerable by participants and their parent/carers. Preliminary data suggest a difference in hyperphagia between patients and controls (d = 0.5), and a relationship between hyperphagia with body mass index standard deviation score (BMISDS) in patients (τ = 0.46). DISCUSSION: These findings demonstrate that eating behaviour research is feasible and acceptable to craniopharyngioma patients and there is an association between BMISDS and hyperphagia in patients. Thus, food approach and avoidance behaviours may be useful targets for interventions to manage obesity in this patient group.

National service evaluation of the quality of care for children and young people with congenital adrenal hyperplasia in the United Kingdom: survey responses from patients and clinicians.

INTRODUCTION: Quantifying differences in service provision for children and young people (CYP) living with Congenital Adrenal Hyperplasia (CAH) across the United Kingdom. METHODS: A national service evaluation using online questionnaires circulated to patients and clinicians from secondary and tertiary UK centres managing CYP with CAH, and via the "Living with CAH" support group mailing list. RESULTS: Total of 195 responses relating to patients aged 0-20 years attending 33 clinics (43 patients, 152 carers), as well as 34 clinicians from 18 trusts working across the 33 clinics. Only 12% of clinicians were 'completely satisfied' with the service provided, compared to 68% of carers and 76% of patients. Whilst 94% of clinicians reported providing formal training to families with CAH, over 80% of both patients and carers reported not attending what they considered formal training. Appetite for further training was higher in carers (86%) than patients (55%), although further 'unsure' responses suggested formal training sessions would likely be well attended. Access to psychological services was difficult for 44% of clinicians. Biochemical monitoring of treatment was broadly in keeping with international guidelines, with 67% of clinicians reporting regular use of dried blood spots, and 12% regular urinary steroid metabolites. CONCLUSION: While there is overall good satisfaction with care provision among patients and carers with CAH in the UK, extra resources addressing the psychological and educational needs about the disease and its management would benefit patients and carers. Improved access to allied health professionals and psychologists will help support families and improve patient outcomes.

Psychological Care of Children and Families with Variations or Differences in Sex Development.

The paediatric clinical psychology literature provides applicable evidence for use in specialist healthcare settings and services. The general approach of psychological care of children and families with paediatric conditions is recognizable as preventative and destigmatizing, aimed to maximize personal agency with shared responsibility for achieving best outcomes via multi-professional teamwork. Recent commentaries regarding healthcare for children with differences in sex development (DSD) have noted service-level pitfalls, including poor teamwork and underuse of early and integrated psychological intervention. Psychological research regarding the variously termed DSD, variations in sex development, variation in sex characteristics, or intersex has historically centred around the assessment of sex differences, gender identity, and the impact of including hormone influences on brain and behaviour. Psychological research in this specialist area has not focussed on the evaluation of specific clinical interventions or psychotherapeutic models but has investigated psychological aspects of multi-professional healthcare provision. There are new goals for psychological care of children with variations or differences in sex development (V/DSD). These require a framework of good communication to enable those receiving care to come to know and articulate their own hopes for treatment and support. Paediatric psychological intervention studies involving larger clinical groups such as diabetes provide evidence applicable to DSD populations. A risk of stigma is recognized as inherent to some physical interventions within routine paediatric care of people with V/DSD. Psychological care and intervention should be aimed at minimizing these risks via questioning and examining their assumed need. Psychological approaches can provide a foundation for ethical and rights-based multi-professional care of children with V/DSD.

Why do parents recommend clitoral surgery? Parental perception of the necessity, benefit, and cost of early childhood clitoral surgery for congenital adrenal hyperplasia (CAH).

Historically, medical management of Congenital Adrenal Hyperplasia (CAH) in girls typically involved feminising surgery, which meant reducing the size and/or visibility of the enlarged clitoris. This practice may have become less routine but remains a common response to genital differences associated with CAH. Parents typically give permission for the child to undergo surgery in early childhood and recommend other parents facing a similar situation do the same. The current report is based on a qualitative content analysis of interviews with sixteen parents whose daughters with CAH had undergone one of two forms of clitoral surgery. We observed that: (i) some parents were initially unconcerned about their child's genital presentation; (ii) in general, clitoral surgery was considered as a readily available and natural response to the child's bodily difference; (iii) the parents acknowledged that there would be some risk but anticipated various benefits; and (iv) there was an absence of ethical considerations when the parents evaluated the various effects of surgery afterwards. We conclude from our analysis that parents of girls with CAH may not receive psychologically and ethically informed counselling to encourage critical reflections prior to authorizing genital surgery.

Rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome - neuro-endocrine tumours (ROHHAD-NET): case series and learning points.

OBJECTIVES: Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation (ROHHAD) is a rare syndrome associated with high morbidity and mortality. Diagnosis is often challenging. We describe three cases of ROHHAD with heterogeneous presentations but some consistent clinical features, including hyperprolactinaemia at diagnosis. We highlight when the diagnosis of ROHHAD should be considered at an early stage. CASE PRESENTATION: All three patients presented between 4 and 6 years old with rapid-onset obesity. They all have central hypoventilation requiring nocturnal BiPAP, varying degrees of hypothalamic dysfunction with hyperprolactinaemia being a consistent feature, and autonomic dysfunction. One patient has a neuro-endocrine tumour (NET) and two have glucose dysregulation. CONCLUSIONS: High prolactin was a consistent early feature. Central hypoventilation and NET may present later and therefore regular sleep studies and screening for NETs are required. A high suspicion of ROHHAD is warranted in patients with rapid, early-onset obesity and hyperprolactinaemia without structural pituitary abnormality.

Quality of Life in Children and Young People With Congenital Adrenal Hyperplasia-UK Nationwide Multicenter Assessment.

CONTEXT: Quality of life (QoL) has been inconsistently reported in children and young people (CYP) with congenital adrenal hyperplasia (CAH). OBJECTIVE: Assess QoL in CYP with CAH in the UK alongside biometric and androgen profiles. DESIGN: To define the evidence base for health care delivery, we conducted a cross-sectional study in CYP with CAH in the UK. Questionnaire results were compared with normative data and between groups, and modelled for association with sex, height, weight, body mass index, or steroid biomarkers of CAH control. SETTING: Tertiary care in 14 UK centers. PATIENTS: Results from 104 patients, 55% female, mean age 12.7 years (SD 3.0), paired responses from parents. INTERVENTIONS: Strengths and Difficulties questionnaire (SDQ) and pediatric QoL questionnaire. MAIN OUTCOME MEASURE: Total QoL scores as assessed by SDQ and a pediatric QoL questionnaire in comparison to normative data. RESULTS: Total scores were worse in parents than normative data, but similar in patients. Patient QoL was rated better in social functioning but worse in emotional, school, and peer domains by patients, and worse in total scores and domains of peer problems, and psychosocial, emotional, and school functioning by parents. Parents consistently scored QoL of their children lower than their child. Larger height-SD score and lower weight-SD score were associated with better QoL. Girls with lower steroid biomarkers had worse SDQ scores. CONCLUSIONS: In CYP with CAH, reduced height, increased weight, and hormonal biomarkers consistent with overtreatment were associated with worse QoL; addressing these problems should be prioritized in clinical management.Clinical Trials Registration Number: SCH/15/088.

Exploring eating behavior and psychological mechanisms associated with obesity in patients with craniopharyngioma: a scoping review protocol.

OBJECTIVE: The objective of the review is to explore the evidence on the behavioral and psychological mechanisms underlying the development of obesity in patients with craniopharyngioma. The review will map the available evidence, identify gaps in the literature, and find avenues of future intervention. INTRODUCTION: Craniopharyngiomas are low-grade intracranial tumors of the supersellar region. Obesity is associated with the tumor or surgery or radiotherapy to treat the tumor; however, the behavioral and psychological processes contributing to that association are not clear. This review will provide a synthesized evidence base of the relevant research. INCLUSION CRITERIA: This review will consider published studies with all types of study designs, including patients with childhood- or adult-onset craniopharyngioma. Articles assessing factors that may impact eating behavior will be included based on the following categories: eating behavior, obesity, neuroimaging, endocrine response, energy expenditure, sleep, and neuropsychology. METHODS: MEDLINE, Embase, and PsycINFO will be searched, in addition to the Cochrane Library, Web of Science, Scopus, ClinicalTrials.gov, NICE evidence search, and International Standard Randomised Controlled Trial Number (ISRCTN). No limits will be placed on the scope of the search. The methodology will follow a three-stage process with two independent reviewers at each stage, including an initial database search, screening of titles and abstracts of retrieved studies, full-text assessment for inclusion criteria, and hand-searching of reference lists. Data will be extracted using a standardized charting form and summarized in tables. The data will be synthesized using a narrative summary and diagrammatic map and will be based on the evidence for each of the proposed research categories.

Health status of children and young persons with congenital adrenal hyperplasia in the UK (CAH-UK): a cross-sectional multi-centre study.

Objective: There is limited knowledge on the onset of comorbidities in congenital adrenal hyperplasia (CAH) during childhood. We aimed to establish the health status of children with CAH in the UK. Design and methods: This cross-sectional multicentre study involved 14 tertiary endocrine UK units, recruiting 101 patients aged 8-18 years with classic 21-hydroxylase deficiency and 83 controls. We analysed demographic, clinical and metabolic data, as well as psychological questionnaires (Strengths and Difficulties (SDQ), Paediatric Quality of Life (PedsQL)). Results: Patient height SDS in relation to mid-parental height decreased with age, indicating the discrepancy between height achieved and genetic potential height. Bone age was advanced in 40.5% patients, with a mean difference from the chronological age of 1.8 (±2.3) years. Patients were more frequently overweight (27%) or obese (22%) compared to controls (10.8% and 10.8%, respectively, P < 0.001). No consistent relationship between glucocorticoid dose and anthropometric measurements or hormonal biomarkers was detected. A small number of patients had raised total cholesterol (3.0%), low HDL (3.0%), raised LDL (7.0%) and triglycerides (5.0%). SDQ scores were within the 'high' and 'very high' categories of concern for 16.3% of patients. 'School functioning' was the lowest PedsQL scoring dimension with a median (interquartile range) of 70 (55-80), followed by 'emotional functioning' with a median of 75 (65-85). Conclusions: Our results show an increased prevalence of problems with growth and weight gain in CAH children and suggest reduced quality of life. This highlights the urgent need to optimise management and monitoring strategies to improve long-term health outcomes.

Genetic Analysis of Pediatric Primary Adrenal Insufficiency of Unknown Etiology: 25 Years' Experience in the UK.

CONTEXT: Although primary adrenal insufficiency (PAI) in children and young people is often due to congenital adrenal hyperplasia (CAH) or autoimmunity, other genetic causes occur. The relative prevalence of these conditions is poorly understood. OBJECTIVE: We investigated genetic causes of PAI in children and young people over a 25 year period. DESIGN SETTING AND PARTICIPANTS: Unpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research centers between 1993 and 2018. We pre-excluded those with CAH, autoimmune, or metabolic causes. We obtained additional data from NR0B1 (DAX-1) clinical testing centers. INTERVENTION AND OUTCOME MEASUREMENTS: Genetic analysis involved a candidate gene approach (1993 onward) or next generation sequencing (NGS; targeted panels, exomes) (2013-2018). RESULTS: A genetic diagnosis was reached in 103/155 (66.5%) individuals. In 5 children the adrenal insufficiency resolved and no genetic cause was found. Pathogenic variants occurred in 11 genes: MC2R (adrenocorticotropin receptor; 30/155, 19.4%), NR0B1 (DAX-1; 7.7%), CYP11A1 (7.7%), AAAS (7.1%), NNT (6.5%), MRAP (4.5%), TXNRD2 (4.5%), STAR (3.9%), SAMD9 (3.2%), CDKN1C (1.3%), and NR5A1/steroidogenic factor-1 (SF-1; 0.6%). Additionally, 51 boys had NR0B1 variants identified through clinical testing. Although age at presentation, treatment, ancestral background, and birthweight can provide diagnostic clues, genetic testing was often needed to define the cause. CONCLUSIONS: PAI in children and young people often has a genetic basis. Establishing the specific etiology can influence management of this lifelong condition. NGS approaches improve the diagnostic yield when many potential candidate genes are involved.

Development and Evaluation of a Psychosocial Intervention for Children and Teenagers Experiencing Diabetes (DEPICTED): a protocol for a cluster randomised controlled trial of the effectiveness of a communication skills training programme for healthcare professionals working with young people with type 1 diabetes.

BACKGROUND: Diabetes is the third most common chronic condition in childhood and poor glycaemic control leads to serious short-term and life-limiting long-term complications. In addition to optimal medical management, it is widely recognised that psychosocial and educational factors play a key role in improving outcomes for young people with diabetes. Recent systematic reviews of psycho-educational interventions recognise the need for new methods to be developed in consultation with key stakeholders including patients, their families and the multidisciplinary diabetes healthcare team. METHODS/DESIGN: Following a development phase involving key stakeholders, a psychosocial intervention for use by paediatric diabetes staff and not requiring input from trained psychologists has been developed, incorporating a communication skills training programme for health professionals and a shared agenda-setting tool. The effectiveness of the intervention will be evaluated in a cluster-randomised controlled trial (RCT). The primary outcome, to be measured in children aged 4-15 years diagnosed with type 1 diabetes for at least one year, is the effect on glycaemic control (HbA1c) during the year after training of the healthcare team is completed. Secondary outcomes include quality of life for patients and carers and cost-effectiveness. Patient and carer preferences for service delivery will also be assessed. Twenty-six paediatric diabetes teams are participating in the trial, recruiting a total of 700 patients for evaluation of outcome measures. Half the participating teams will be randomised to receive the intervention at the beginning of the trial and remaining centres offered the training package at the end of the one year trial period. DISCUSSION: The primary aim of the trial is to determine whether a communication skills training intervention for specialist paediatric diabetes teams will improve clinical and psychological outcomes for young people with type 1 diabetes. Previous research indicates the effectiveness of specialist psychological interventions in achieving sustained improvements in glycaemic control. This trial will evaluate an intervention which does not require the involvement of trained psychologists, maximising the potential feasibility of delivery in a wider NHS context. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61568050.